January 04, 2011

Cell Biology This Week

The blood-brain barrier (BBB) is created by special tight junctions between the endothelial cells of the brain’s vasculature. This barrier is meant to keep out unwanted intruders, like bacteria, from the brain. How the barrier and its selective permeability are set up are of inherent interest. But beyond that, how some bacteria - such as the Gram-negative Neisseria meningitides - breach this divide to infect the brain and cause meningitis is also fascinating. How do the bacteria penetrate this otherwise efficient endothelial barrier? It is known that the bacteria in the blood stream adhere to blood vessel walls using appendages called Type IV pili. Here they multiply and form colonies, which manipulate signaling and the actin cytoskeleton in the endothelial cells. Now Coureuil et al. provide new molecular insight into how this bacterium gets past the BBB. The same group had shown previously that N. meningitidis stimulates the relocalization of intercellular junction components, producing gaps in the endothelial layer through which the bacterial can squeeze through to infect the brain. Now, these authors show that many of the events involved in this process are dependent on the G protein-coupled receptor β2AR and downstream components like β-arrestins, both of which accumulate at the plasma membrane under the bacterial colonies. β2AR and β-arrestins are required for the ability of the bacterium to resist the shear forces that would otherwise sweep them away in the bloodstream. β-arrestins act by promoting the docking and activation of Src to induce the formation of actin-rich protrusions that protect the bacteria from the shear forces. In addition, Coureuil et al. show that both β2AR and β-arrestins are also required for the relocalization of junction proteins: β-arrestins interact with and recruit proteins like VE-cadherin to sites of bacterial entry and away from normal intercellular junctions. Importantly, ligand-induced endocytosis of β2AR reduces both sustained adhesion of the bacterium and their ability to cross the barrier, a finding that could hold some therapeutic potential.

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